Nicotinic acid receptor agonists impair myocardial contractility by energy starvation.

Nicotinic acid receptor agonists have previously been shown to cause acute reductions in cardiac contractility. We sought to uncover the changes in cardiac metabolism underlying these alterations in function. In nine humans, we recorded cardiac energetics and function before and after a single oral dose of nicotinic acid using cardiac MRI to demonstrate contractile function and Phosphorus-31 (31 P) magnetic resonance spectroscopy to demonstrate myocardial energetics. Nicotinic Acid 400 mg lowered ejection fraction by 4% (64 ± 8% to 60 ± 7%, P = .03), and was accompanied by a fall in phosphocreatine/ATP ratio by 0.4 (2.2 ± 0.4 to 1.8 ± 0.1, P = .04). In four groups of eight Wistar rats, we used pyruvate dehydrogenase (PDH) flux studies to demonstrate changes in carbohydrate metabolism induced by the nicotinic acid receptor agonist, Acipimox, using hyperpolarized Carbon-13 (13 C) magnetic resonance spectroscopy. In rats which had been starved overnight, Acipimox caused a fall in ejection fraction by 7.8% (67.5 ± 8.9 to 60 ± 3.1, P = .03) and a nearly threefold rise in flux through PDH (from 0.182 ± 0.114 to 0.486 ± 0.139, P = .002), though this rise did not match pyruvate dehydrogenase flux observed in rats fed carbohydrate rich chow (0.726 ± 0.201). In fed rats, Acipimox decreased pyruvate dehydrogenase flux (to 0.512 ± 0.13, P = .04). Concentration of plasma insulin fell by two-thirds in fed rats administered Acipimox (from 1695 ± 891 ng/L to 550 ± 222 ng/L, P = .005) in spite of glucose concentrations remaining the same. In conclusion, we demonstrate that nicotinic acid receptor agonists impair cardiac contractility associated with a decline in cardiac energetics and show that the mechanism is likely a combination of reduced fatty acid availability and a failure to upregulate carbohydrate metabolism, essentially starving the heart of fuel.

Differences in the serum metabolome and lipidome identify potential biomarkers for seronegative rheumatoid arthritis versus psoriatic arthritis.

OBJECTIVES: The differential diagnosis of seronegative rheumatoid arthritis (negRA) and psoriasis arthritis (PsA) is often difficult due to the similarity of symptoms and the unavailability of reliable clinical markers. Since chronic inflammation induces major changes in the serum metabolome and lipidome, we tested whether differences in serum metabolites and lipids could aid in improving the differential diagnosis of these diseases. METHODS: Sera from negRA and PsA patients with established diagnosis were collected to build a biomarker-discovery cohort and a blinded validation cohort. Samples were analysed by proton nuclear magnetic resonance. Metabolite concentrations were calculated from the spectra and used to select the variables to build a multivariate diagnostic model. RESULTS: Univariate analysis demonstrated differences in serological concentrations of amino acids: alanine, threonine, leucine, phenylalanine and valine; organic compounds: acetate, creatine, lactate and choline; and lipid ratios L3/L1, L5/L1 and L6/L1, but yielded area under the curve (AUC) values lower than 70%, indicating poor specificity and sensitivity. A multivariate diagnostic model that included age, gender, the concentrations of alanine, succinate and creatine phosphate and the lipid ratios L2/L1, L5/L1 and L6/L1 improved the sensitivity and specificity of the diagnosis with an AUC of 84.5%. Using this biomarker model, 71% of patients from a blinded validation cohort were correctly classified. CONCLUSIONS: PsA and negRA have distinct serum metabolomic and lipidomic signatures that can be used as biomarkers to discriminate between them. After validation in larger multiethnic cohorts this diagnostic model may become a valuable tool for a definite diagnosis of negRA or PsA patients.

Role of Magnetic Resonance Spectroscopy in Evaluation of Cerebral Metabolic Status Before and After Carotid Endarterectomy/Thromboendarterectomy and Carotid Artery Stenting in Patients with Asymptomatic Critical Internal Carotid Artery Stenosis.

BACKGROUND The relative efficacy of carotid endarterectomy (CEA)/thromboendarterectomy (TEA) and carotid artery stenting (CAS) already has been compared in randomized controlled trials and a meta-analysis, but only limited data exist describing the status of cerebral metabolism before and after these interventions. The aim of the present study was to compare metabolic changes before and after treatment of carotid stenosis and assess their potential clinical implications.   MATERIAL AND METHODS Patients with asymptomatic unilateral critical internal CAS were imaged with proton 3T magnetic resonance spectroscopy (H-MRS) because the technique is more sensitive than regular magnetic resonance imaging for detection of the early signs of ischemic events. Abnormal metabolite ratios detected with H-MRS may precede actual morphological changes associated with hypoperfusion as well as reperfusion changes. Ipsilateral and contralateral middle cerebral artery vascular territories were both evaluated before and after vascular intervention. H-MRS was performed within 24 h before and after surgery. Correlations in the metabolic data from H-MRS for N-acetylaspartic acid (NAA)+N-acetylaspartylglutamate, creatinine (Cr)+phosphocreatinine, and phosphocholine+glycerophosphocholine (Cho) were sought. RESULTS H-MRS voxels from 11 subjects were analyzed. Values for dCho/CrI, dCho/CrC and Cho/Naal (P<0.001) were significantly higher ipsilaterally than contralaterally. Ratios for dNaa/ChoC and Cho/NaaC were significantly higher on the non-operated side (P<0.001). CONCLUSIONS H-MRS may be helpful for assessment of patients with CAS, particularly because unlike other modalities, it reveals postoperative changes in metabolic brain status. Initial results indicate the important role of perioperative neuroprotective treatment.

Creatine and phosphocreatine mapping of mouse skeletal muscle by a polynomial and Lorentzian line-shape fitting CEST method.

PURPOSE: To obtain high-resolution Cr and PCr maps of mouse skeletal muscle using a polynomial and Lorentzian line-shape fitting (PLOF) CEST method. METHODS: Wild-type mice and guanidinoacetate N-methyltransferase-deficient (GAMT-/-) mice that have low Cr and PCr concentrations in muscle were used to assign the Cr and PCr peaks in the Z-spectrum at 11.7 T. A PLOF method was proposed to simultaneously extract and quantify the Cr and PCr by assuming a polynomial function for the background and 2 Lorentzian functions for the CEST peaks at 1.95 ppm and 2.5 ppm. RESULTS: The Z-spectra of phantoms revealed that PCr has 2 CEST peaks (2 ppm and 2.5 ppm), whereas Cr only showed 1 peak at 2 ppm. Comparison of the Z-spectra of wild-type and GAMT-/- mice indicated that, contrary to brain, there was no visible protein guanidinium peak in the skeletal-muscle Z-spectrum, which allowed us to extract clean PCr and Cr CEST signals. High-resolution PCr and Cr concentration maps of mouse skeletal muscle were obtained by the PLOF CEST method after calibration with in vivo MRS. CONCLUSIONS: The PLOF method provides an efficient way to map Cr and PCr concentrations simultaneously in the skeletal muscle at high MRI field.

Simultaneous quantitative analysis of phosphocreatine, creatine and creatinine in plasma of children by HPLC-MS/MS method: Application to a pharmacokinetic study in children with viral myocarditis.

A simple and rapid HPLC-MS/MS method was developed and validated for simultaneous measurement of phosphocreatine and its metabolites creatine and creatinine in children's plasma. A 50 µL aliquot of plasma was prepared by protein precipitation with acetonitrile-water (1000 µL, 1:1, v/v) followed by separation on a Hypersil Gold C18 column (35°C) with gradient mobile phase consisting of 2 mm ammonium acetate aqueous solution (pH 10) and methanol at a flow rate of 0.3 mL/min and analyzed by mass spectrometry in both positive (phosphocreatine) and negative (creatine and creatinine) ion multiple reaction monitoring mode. Good linearity (r > 0.99) was obtained for the three analytes. The intra-day and inter-day values of CV were <5.46% (-13.09% ≤ RE ≤ 2.57%). The average recoveries of the three analytes were 70.9-97.5%. No obvious impact was found for the quantitation of three analytes in normal, hemolyzed and hyperlipemic plasma. In the end, this method was successfully applied to a pharmacokinetic study of phosphocreatine in children (six cases) with viral myocarditis of children after intravenous infusion of 2 g of the test drug. The pharmacokinetc parameters of phosphocreatine/creatine were as follows: t1/2 0.24/0.83 h, Tmax 0.49/0.55 h, Cmax 47.34/59.29 µg/mL, AUClast 17.07/59.63 h µg/mL, AUCinf 17.16/79.01 h µg/mL and MRT 0.29/0.67 h.

Adiabatic excitation for 31 P MR spectroscopy in the human heart at 7 T: A feasibility study.

PURPOSE: Phosphorus magnetic resonance spectroscopy (31 P-MRS) provides a unique tool for assessing cardiac energy metabolism, often quantified using the phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio. Surface coils are typically used for excitation for 31 P-MRS, but they create an inhomogeneous excitation field across the myocardium, producing undesirable, spatially varying partial saturation. Therefore, we implemented adiabatic excitation in a 3D chemical shift imaging (CSI) sequence for cardiac 31 P-MRS at 7 Tesla (T). METHODS: We optimized an adiabatic half passage pulse with bandwidth sufficient to excite PCr and γ-ATP together. In addition, the CSI sequence was modified to allow interleaved excitation of PCr and γ-ATP, then 2,3-DPG, to enable PCr/ATP determination with blood correction. Nine volunteers were scanned at 2 transmit voltages to confirm that measured PCr/ATP was independent of B1+ (i.e. over the adiabatic threshold). Six septal voxels were evaluated for each volunteer. RESULTS: Phantom experiments showed that adiabatic excitation can be reached at the depth of the heart using our pulse. The mean evaluated cardiac PCr/ATP ratio from all 9 volunteers corrected for blood signal was 2.14 ± 0.16. Comparing the two acquisitions with different voltages resulted in a minimal mean difference of -0.005. CONCLUSION: Adiabatic excitation is possible in the human heart at 7 T, and gives consistent PCr/ATP ratios. Magn Reson Med 78:1667-1673, 2017. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Comparison of methods for estimating glomerular filtration rate in head and neck cancer patients treated with cisplatin.

Cisplatin is a chemotherapeutic agent widely used in the treatment of various solid tumors. Cisplatin induces nephrotoxicity and may lead to long-term reduction of kidney function. Consequently, determination of glomerular filtration rate (GFR) is used to monitor potential kidney damage. This study aimed to compare two commonly used algorithms for estimating GFR (eGFR) from plasma creatinine (PCr) with 51Cr-EDTA clearance (CrCl) as a reference method. This was a retrospective single center study of 94 head and neck cancer patients treated with cisplatin. CrCl was performed once before, during, and after treatment, and PCr was measured concurrently. eGFR was assessed from PCr applying the Cockcroft-Gault (CG) and the Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) equations. Agreement was assessed applying the statistical methods of Bland and Altman. A predefined limit of clinically acceptable variation between CrCl and eGFR of 14% was applied. Comparison of CrCl and eGFRCKD revealed a positive slope of the linear regression line, suggesting proportional bias (p < 0.001). No systematic bias was found for eGFRCG. Pre-treatment, 42 (46%), 53 (56%) and 48 (53%) observations were within the clinically acceptable limit of variation for standardized eGFRCKD, BSA corrected eGFRCKD, and eGFRCG, respectively. The observed body weight changes were significant. In conclusion, estimated GFRCKD cannot sufficiently replace CrCl in the assessment of GFR during treatment with cisplatin due to systematic bias. Consequently, if CrCl is unavailable, then the CG equation is the better choice provided proper attention is paid to the large variation between methods.

Antiarrhythmic effect of uridine and uridine-5'-monophosphate in acute myocardial ischemia.

Experiments on rats with acute myocardial ischemia accompanied by early postocclusive arrhythmias have shown normalizing, energy-stabilizing, and antiarrhythmic effects of uridine and uridine-5'-monophosphate. The drugs decreased lactate and restored reserves of glycogen and creatine phosphate depleted by ischemia. Uridine and uridine-5'-monophosphate significantly decreased the severity of ventricular arrhythmias. Both drugs reduced the incidence and duration of fibrillation. Uridine -5'-monophosphate demonstrated most pronounced antifibrillatory effectiveness. We hypothesize that the antiarrhythmic effect of the drugs is determined by their capacity to activate energy metabolism.

Gender-related alterations of serum trace elements and neurometabolism in the anterior cingulate cortex of patients with major depressive disorder.

BACKGROUND: It is widely known that sex differences have a significant impact on patients with major depressive disorder (MDD). This study aims to evaluate the sex-related connection between serum trace elements and changes in neurometabolism in the anterior cingulate cortex (ACC) of MDD patients. METHODS: 109 untreated MDD patients and 59 healthy controls underwent proton magnetic resonance spectroscopy (1H-MRS) under resting conditions. We measured metabolic ratios in the ACC from both sides. Additionally, venous blood samples were taken from all participants to detect calcium (Ca), phosphorus, magnesium (Mg), copper (Cu), ceruloplasmin (CER), zinc (Zn), and iron (Fe) levels. We performed association and interaction analyses to explore the connections between the disease and gender. RESULTS: In individuals with MDD, the Cu/Zn ratio increased, while the levels of Mg, CER, Zn and Fe decreased. Male MDD patients had lower Cu levels, while female patients had an increased Cu/Zn ratio. We observed significant gender differences in Cu, CER and the Cu/Zn ratio in MDD. Male patients showed a reduced N-acetyl aspartate (NAA)/phosphocreatine + creatine (PCr + Cr) ratio in the left ACC. The NAA/PCr + Cr ratio decreased in the right ACC in patients with MDD. In the left ACC of male MDD patients, the Cu/Zn ratio was inversely related to the NAA/PCr + Cr ratio, and Fe levels were negatively associated with the GPC + PC/PCr + Cr ratio. CONCLUSIONS: Our findings highlight gender-specific changes in Cu homeostasis among male MDD patients. The Cu/Zn ratio and Fe levels in male MDD patients were significantly linked to neurometabolic alterations in the ACC.

Metabolomic signatures in guinea pigs infected with epidemic-associated W-Beijing strains of Mycobacterium tuberculosis.

With the understanding that the laboratory propagated strain of Mycobacterium tuberculosis H37Rv is of modest virulence and is drug susceptible, in the present study, we performed a nuclear magnetic resonance-based metabolomic analysis of lung tissues and serum obtained from guinea pigs infected by low dose aerosol exposure to clinical isolates of Mycobacterium tuberculosis. High Resolution Magic Angle Spinning NMR coupled with multivariate statistical analysis of 159 lung tissues obtained from multiple locations of age-matched naïve and 30 and 60 days of infected guinea pig lungs revealed a wide dispersal of metabolic patterns, but within these, distinct clusters of signatures could be seen that differentiated between naive control and infected animals. Several metabolites were identified that changed in concert with the progression of each infection. Major metabolites that could be interpreted as indicating host glutaminolysis were consistent with activated host immune cells encountering increasingly hypoxic conditions in the necrotic lung lesions. Moreover, glutathione levels were constantly elevated, probably in response to oxygen radical production in these lesions. Additional distinct signatures were also seen in infected serum, with altered levels of several metabolites. Multivariate statistical analysis clearly differentiated the infected from the uninfected sera; in addition, Receiver Operator Characteristic curve generated with principal component 1 scores showed an area under the curve of 0.908. These data raise optimism that discrete metabolomic signatures can be defined that can predict the progression of the tuberculosis disease process, and form the basis of an innovative and rapid diagnostic process.

[Pharmacokinetics and metabolic disposition of exogenous phosphocreatine in rats].

This article is report the study of the pharmacokinetics and metabolic disposition of exogenous phosphocreatine (PCr) in rats by means of an ion-pair HPLC-UV assay. PCr and its metabolite creatine (Cr) and related-ATP in rat plasma and red blood cell (RBC) were simultaneously determined. A blank plasma and RBC were initially run for baseline subtraction. Plasma and RBC samples were deproteinized with 6% PCA prior to HPLC. Following i.v. administration of PCr 500 mg x kg(-1) and 1 000 mg x kg(-1) the C-T curve could be described by the two-compartment model with t1/2beta 22.5-23.3 min, V(d) 0.956 4-0.978 6 L x kg(-1), CL 0.029 L. kg(-1) x min(-1). The Cr as PCr degraded product appeared as early as 2 min post i.v. dosing with t(max) 20 min, t1/2kappa (m) 40.6-42.7 min and f(m) 60%-76%. After po administration of PCr, the parent drug in plasma was undetectable, but the metabolite Cr was detected with t(max) 65-95 min, t1/2kappa (m) 56.0-57.7 min, metabolite-based bioavailability F(m) 55.02%-62.31%. PCr i.v. administration resulted in significant elevation of ATP level in RBC but not in plasma, the related-ATP in RBC was characterized by t(max) 68-83 min, t1/2kappa 49-52 min. In RBC no exogenous PCr was found but Cr was detected following i.v. administration of PCr, with the t(max) 120 min and t1/2k (m) 70 min for Cr. The above results indicate that PCr eliminates and bio-transforms in body very rapidly; K > K(m) confers ERL, instead of FRL, type upon the metabolic disposition of Cr. Following po administration of PCr, the degraded product Cr is absorbed but not the parent drug PCr. The formed Cr can be accounted for by most of i.v. and po PCr. Intravenous dosing leads apparently increased and sustained Cr and related-ATP concentration in RBC.

Creatine kinase expression and creatine phosphate accumulation are developmentally regulated during differentiation of mouse and human monocytes.

We have studied the expression of creatine kinase (CK) and the accumulation of creatine phosphate during the differentiation of human and mouse peripheral blood monocytes. Mouse monocytes cultured for 24 h do not contain detectable levels of CK and creatine phosphate. However, resident tissue macrophages and inflammatory elicited macrophages obtained from the peritoneal cavities of mice have 70 and 300 mU per mg protein of CK activity and contain 3 and 6 mol of creatine phosphate per mol of ATP, respectively. The major isozyme of CK in these cells has been identified as the brain form. These findings suggest that the differentiation of monocytes into macrophages is associated with the expression of CK and the accumulation of creatine phosphate. We have found a similar pattern in human monocytes. Human blood monocytes, maintained in culture for 24 or 48 h, do not contain detectable levels of CK or creatine phosphate. Monocyte-derived macrophages (monocytes maintained in tissue cultures for 1 to 2 wk) have up to 100 mU per mg protein of CK activity and contain 0.5 mol of creatine phosphate per mol of ATP. Human macrophages express multiple isozymes of CK including the brain (BB) and possibly the mitochondrial forms of this enzyme. Thus, the expression of CK and the accumulation of creatine phosphate in human monocytes is induced by their in vitro cultivation. The induction of CK during in vitro cultivation occurs independently of the concentration of creatine in the medium. However, the size of the creatine phosphate pool varies with respect to extracellular creatine concentration. Creatine phosphate and CK are not detectable in freshly isolated human lymphocytes, polymorphonuclear leukocytes or erythrocytes, but are found in freshly isolated human platelets.

Relationship between cerebral oxygenation and phosphorylation potential during secondary energy failure in hypoxic-ischemic newborn piglets.

The aim of this study was to evaluate the hypothesis that cerebral hemoglobin (Hb) oxygenation is related to phosphorylation potential during primary and secondary cerebral energy failure in newborn infants who have experienced birth asphyxia. We subjected newborn piglets to severe transient cerebral hypoxic-ischemia followed by resuscitation and examined cerebral energy metabolism by 31P-magnetic resonance spectroscopy and evaluated changes in cerebral Hb oxygen saturation (ScO2) using full-spectrum near-infrared spectroscopy before, during, and up to 54 h after the hypoxic-ischemic insult. ScO2 was significantly decreased during the hypoxic-ischemic insult compared with baseline values. During secondary energy failure, piglets were separated based on the relationship between the ratio of phosphocreatine to inorganic phosphate and ScO2; those with a negative correlation were less injured than those with a positive correlation. These results indicate that changes in ScO2 as measured by near-infrared spectroscopy are related to phosphorylation potential during secondary energy failure in asphyxiated infants.

Deoxygenated hemoglobin/myoglobin kinetics of forearm muscles from rest to exercise in patients with chronic obstructive pulmonary disease.

Exercise capacity is frequently decreased in patients with chronic obstructive pulmonary disease (COPD), and muscle dysfunction is one factor in this reduction. Studies using (31)-phosphorus magnetic resonance spectroscopy ((31)P-MRS) have shown that phosphocreatine (PCr) and muscle pH (pHi) are significantly decreased in patients with COPD during mild exercise, suggesting the early activation of anaerobic glycolysis in their muscles. Thus, muscle oxygenation states during exercise might differ between patients with COPD and healthy individuals. We simultaneously measured oxygenation state and pHi in the muscles of patients with COPD during the transition from rest to exercise (on-transition) using near infrared spectroscopy (NIRS) and (31)P-MRS. Sixteen patients with COPD (aged 68.6 +/- 7.5 years) and 7 healthy males (controls; aged 63.3 +/- 7.5 years) performed dynamic handgrip exercise (lifting a weight by gripping at a rate of 20 grips per min for 3 min). Patients were classified based on pHi data at the completion of exercise as having a normal (>or= 6.9; n = 8) or a low (< 6.9; n = 8) pHi. The deoxygenated hemoglobin/myoglobin (deoxy-Hb/Mb) in NIRS recordings remained constant or slightly decreased initially (time delay), then increased to reach a plateau. We calculated the time delay and the time constant of deoxy-Hb/Mb kinetics during the on-transition. The time delay was shorter in the group with a low pHi than in the controls. These findings might reflect a slower increase in O(2) delivery in patients with a low pHi, which might partly account for altered muscle energy metabolism.

[Dietary SkQ1 supplement reduces myocardial ischemia- reperfusion injury in rats in vivo].

To examine whether nutritional supplementation with SkQ1 can reduce myocardial ischemia-reperfusion injury in vivo, Wistar rats were fed a regular diet supplemented with different doses of SkQ1 for two or three weeks. Control groups of rats were fed the same diet supplemented with NaBr. Anaesthetized rats were subjected to 40-min regional myocardial ischemia and 1-h reperfusion. Myocardial infarct size was measured by 2,3,5-triphenyl tetrazolium chloride (TTC) staining method. SkQ1-fed rats (125 nmol/kg/day for two weeks and 250 nmol/kg/day for two and three weeks) revealed significantly smaller myocardial infarction and less lactate dehydrogenase (LDH) and creatine kinase-MB fraction (CK-MB) activity elevations in plasma at the end of reperfusion compared with the controls. This effect was combined with improvement of energy state of the area at risk at the end of reperfusion, namely, augmentation of adenine nucleotide content, two-fold increase in phosphocreatine, reduction of lactate accumulation and decrease of lactate/pyruvate ratio in myocardial tissue. Therefore, nutritional supplementation with SkQ1 renders the hearts resistant to ischemia-reperfusion injury affecting oxidative metabolism of postischemic cardiomyocytes.

Energy System Contributions in Upper and Lower Body Wingate Tests in Highly Trained Athletes.

PURPOSE: This study compared the energy system contributions and relationship between mechanical and energy system variables in upper and lower body Wingate tests (WAnT) in judo athletes. METHOD: Eleven male judo athletes (18 ± 1 years, 174.3 ± 5.3 cm, 72.6 ± 9.9 kg, 11.8 ± 1.7% body fat) attended two laboratory sessions to perform two WAnT (upper and lower body) and two incremental tests (upper and lower body). The energy contributions of the oxidative, glycolytic, and phosphagen (ATP-PCr) systems were estimated based on oxygen consumption ( V˙O2 ) during WAnT, delta of lactate, and the fast phase of excess V˙O2 , respectively. RESULTS: The upper and lower body presented similar results of oxidative (21 ± 4% vs 23 ± 3%) and ATP-PCr system contributions (29 ± 6% vs 32 ± 5%). The glycolytic system contribution (50 ± 5% vs 45 ± 4%) was higher in the upper body. The variance of mechanical variables in upper body was explained by glycolytic (R2 = 0.49-0.62) and oxidative systems (R2 = 0.44-0.49), whereas the variance of mechanical variables in lower body was explained by ATP-PCr (R2 = 0.41-0.55) and glycolytic systems (R2 = 0.62-0.94). CONCLUSIONS: During WAnT, the glycolytic system presented the major energy contribution, being higher in the upper body. Moreover, mechanical and energy system variables presented a distinct relationship when comparing upper and lower body WAnT.

A test to evaluate the physical impact on technical performance in soccer.

The aim of the study was to develop and examine a test for evaluation of the physical and technical capacity of soccer players. Fourteen youth elite (YE) and seven sub-elite (SE) players performed a physical and technical test (PT-test) consisting of 10 long kicks interspersed with intense intermittent exercise. In addition, a control test (CON-test) without intense exercise was performed. In both cases, the test result was evaluated by the precision of the 10 kicks. The players also performed the Yo-Yo intermittent recovery test level 2 (Yo-Yo IR2). For the SE-players, blood samples were obtained and heart rate was measured before, during, and after the PT-test. A muscle biopsy was collected before and after the PT-test. Coefficient of variation for the PT- and CON-test was 11.7% and 16.0%, respectively. The YE-players performed better (P < 0.05) than the SE-players in both the PT-test (16.3 +/- 0.8 (+/-SE) vs. 13.2 +/- 1.3 points) and CON-test (24.4 +/- 0.7 vs. 20.5 +/- 1.6 points) with no difference in the relative PT-test result (PT-test/CON-test: 0.63 +/- 0.03 vs. 0.64 +/- 0.03). Summed performance of the first 5 repetitions was higher (P < 0.05) than for the last 5 repetitions (8.4 +/- 0.6 vs. 6.9 +/- 0.5; n = 20). The YE-players performed better (P < 0.05) than the SE-players during Yo-Yo IR2 (1023 +/- SE vs. 893 +/- SE m). The mean heart rate during the PT-test was 173 +/- 4 b.p.m. (90 +/- 2% of HRmax). Blood lactate, glucose, and ammonia reached 5.6 +/- 0.7, 6.2 +/- 0.6 mmol L(-1), and 76 +/- 11 umol L(-1) at the end of the test, respectively. After the test muscle CP, glycogen and lactate was 52.9 +/- 6.6, 354 +/- 39, and 25.3 +/- 5.9 mmol kg(-1) d.w., respectively. In summary, the PT-test can be used to evaluate a soccer player's technical skills under conditions similar to intense periods of a soccer game.

Exercise Response Variations in Skeletal Muscle PCr Recovery Rate and Insulin Sensitivity Relate to Muscle Epigenomic Profiles in Individuals With Type 2 Diabetes.

OBJECTIVE: Some individuals with type 2 diabetes do not reap metabolic benefits from exercise training, yet the underlying mechanisms of training response variation are largely unexplored. We classified individuals with type 2 diabetes (n = 17) as nonresponders (n = 6) or responders (n = 11) based on changes in phosphocreatine (PCr) recovery rate after 10 weeks of aerobic training. We aimed to determine whether the training response variation in PCr recovery rate was marked by distinct epigenomic profiles in muscle prior to training. RESEARCH DESIGN AND METHODS: PCr recovery rate as an indicator of in vivo muscle mitochondrial function in vastus lateralis (31P-magnetic resonance spectroscopy), insulin sensitivity (M-value; hyperinsulinemic-euglycemic clamp), aerobic capacity (Vo2peak), and blood profiles were determined pretraining and post-training. Muscle biopsies were performed pretraining in vastus lateralis for the isolation of primary skeletal muscle cells (HSkMCs) and assessments of global DNA methylation and RNA sequencing in muscle tissue and HSkMCs. RESULTS: By design, nonresponders decreased and responders increased PCr recovery rate with training. In nonresponders, insulin sensitivity did not improve and glycemic control (HbA1c) worsened. In responders, insulin sensitivity improved. Vo2peak improved by ∼12% in both groups. Nonresponders and responders were distinguished by distinct pretraining molecular (DNA methylation, RNA expression) patterns in muscle tissue, as well as in HSkMCs. Enrichment analyses identified elevations in glutathione regulation, insulin signaling, and mitochondrial metabolism in nonresponders pretraining, which was reflected in vivo by higher pretraining PCr recovery rate and insulin sensitivity in these same individuals. CONCLUSIONS: A training response variation for clinical risk factors in individuals with type 2 diabetes is reflected by distinct basal myocellular epigenomic profiles in muscle tissue, some of which are maintained in HSkMCs, suggesting a cell-autonomous underpinning. Our data provide new evidence to potentially shift the diabetes treatment paradigm for individuals who do not benefit from training, such that supplemental treatment can be designed.

Failure of Rhodiola rosea to alter skeletal muscle phosphate kinetics in trained men.

Rhodiola rosea is an herbal supplement purported to improve resistance to stressors and to enhance physical performance, potentially by improving adenosine triphosphate (ATP) turnover. Phosphocreatine (PCr) kinetics serves as a reflection of ATP turnover. The purpose of this investigation was to examine the effect of R rosea ingestion on human skeletal muscle PCr recovery after exhaustive exercise. Twelve resistance-trained men, aged 19 to 39 years, completed incremental forearm wrist flexion exercise to volitional fatigue, once after ingesting 1500 mg R rosea per day for 4 days, and once after ingesting an equivalent placebo dose. During exercise and recovery from exercise, muscle phosphates were examined using phosphorus 31 nuclear magnetic resonance spectroscopy. [PCr] during recovery was fit with a monoexponential function, and the resulting rate constants (k) were compared between groups. Rating of perceived exertion per stage and time to exhaustion were also compared between groups. For R rosea, k=0.3744+/-0.1532, whereas for placebo, k=0.3956+/-0.2238. Although rating of perceived exertion significantly increased within groups as workload increased, it did not differ between conditions, nor did time to exhaustion (R rosea, 10.71+/-0.54 minutes; placebo, 10.48+/-0.68 minutes). Estimates of [PCr] at time 0, 5, 10, 15, and 20 minutes of recovery were nearly identical between groups. In summary, there were no significant differences between groups for any of theparameters measured. Based on these results, we conclude that R rosea ingestion does not improve ATP turnover during or immediately after exercise.

Effects of hydralazine-induced vasodilation on the energy metabolism of murine tumors studied by in vivo 31P-nuclear magnetic resonance spectroscopy.

The effects of hydralazine on tumor energy metabolism and on some cardiovascular parameters were measured. Tumor energy metabolism was studied in C3Hf/Sed mice with isotransplants of a spontaneous murine fibrosarcoma (FSaII, congruent to 100 mm3 in volume) and 31P-NMR. Cardiovascular parameters were measured in anesthetized C3Hf/Sed mice via intracarotid catheter. Hydralazine doses of 0.25 mg/kg given ip caused an increase of the phosphocreatine to inorganic phosphate ratio (PCr: Pi) in 5 of 6 animals. These doses had minimal effects on mean arterial blood pressure, though there may have been an increased cardiac output due to a decreased afterload. Hydralazine doses greater than or equal to 2.0 mg/kg given ip were associated with a decrease in PCr, nucleotide triphosphate, and pH, and an increase in Pi (P less than .01 for control vs. 10 mg hydralazine/kg). This substantial decrease in high-energy phosphates was associated with a pronounced decrement in mean arterial blood pressure. These findings provide a rational basis for the study in experimental systems of hydralazine-induced enhancement of cell killing by hyperthermia and by agents toxic to hypoxic cells. Further, these results can be taken as a sign that hydralazine should be used with care in patients undergoing radiation treatment.